Opioids constitute the single most useful and commonly used class of analgesics for pain of moderate or severe intensity. The use of opioids for chronic pain has grown very rapidly in recent years, yet we have a poor understanding of some of the limitations of this form of therapy. Recently it has been reported both from work in humans and animal models that the chronic administration of opioids can lead to a state of hyperalgesia termed opioid-induced hyperalgesia (OIH). This phenomenon may limit the utility of opioids used for the treatment of chronic pain. Our understanding of OIH to this point has relied primarily on the use of pharmacological tools and has grown to include data supporting roles for monoxide signaling systems like heme oxygenase and nitric oxide synthase, the NMDA receptor, dynorphin and alterations in various nociceptive and regulatory pathways. We lack, however, data concerning the genetics of susceptibility to OIH. Where employed by other investigators genetic studies involving mice have provided unique incites into the mechanisms of nociception and analgesia. We propose to employ a genomic mapping strategy in which behavioral observations concerning the susceptibility of several strains of mice to the development of OIH after the repeated administration of morphine are coupled with a recently developed computational algorithm and a single nucleotide polymorphism (SNP) database to identify segments of the genome likely to be involved in susceptibility to OIH. In addition, we will be able to collect data concerning the basal sensitivity of these strains to morphine, as well as the extent of tolerance developed and the degree of physical dependence induced by repeated administration of this opioid. Thus a second dimension of the studies will be to make mechanistic comparisons between the phenomena of OIH, morphine induced analgesia, tolerance and physical dependence. These data will be collected over the two years of support requested (stage 1) and will form the foundation for stage 2 studies in which specific experiments will be designed to further refine our map and to examine the roles of genes chosen from the high probability mapping regions in the development of OIH. Thus our overall goal is to bring a unique and complimentary approach to the ongoing studies of OIH by using genomics to objectively identify genes involved in this phenomenon.